The present invention relates to a stable, non-aqueous solution containing tolnaftate for topical application in the treatment of fungal infections.
A fungus is a type of microscopic plant. Fungi include dermatophytes, yeasts and molds characterized by a simple cell structure and the absence of chlorophyll. A dermatophyte is a type of fungus that invades and lives upon the skin or in the hair or nails, resulting in a fungal infection. When the fungal infection involves the scalp, it is known as tinea capitis; when it involves the feet, it is known as tinea pedis (athlete's foot); when it occurs on the body, it is known as tinea corporis; and when it occurs on the groin, it is known as tinea cruris. A fungal infection of the nails in which the invasion is restricted to white patches or pits on the nail surface or the lateral or distal edges of the nail are first involved, followed by establishment of the infection beneath the nail plate, is known as tinea unguium. This type of infection is also known as dermatophytic onychomycosis or ringworm of the nail.
A variety of pharmaceutical compositions are available for the treatment of fungal infections. Such compositions include potassium iodide, Whitfield's ointment (a mixture of benzoic and salicylic acids), undecylenic acid, antibiotics (e.g., nystatin and amphotericin B), griseofulvin and imidazole antifungal agents such as miconazole, and others. Other antifungal agents include haloprogin, tolnaftate, naftifine and ciclopirox.
Tolnaftate is a well-known topical antifungal agent of very low mammalian toxicity. Tolnaftate has an oral LD.sub.50 in mice and rats of &gt;10 g/kg and &gt;6 g/kg, respectively. Merck Index, 11 Ed., p. 1499.
Tolnaftate has the chemical formula shown below: ##STR1## Tolnaftate has a melting point of 110.5.degree. to 111.5.degree. C. and is insoluble in water, sparingly soluble in methanol and ethanol and soluble in chloroform and acetone. Id. The synthesis of tolnaftate is described in U.S. Pat. No. 3,334,126, which is hereby incorporated by reference.
In preparing a formulation for the topical application of tolnaftate for the treatment of fungal infections, it is desirable that the formulation be emollient penetrating, dry rapidly on the skin, be non-irritating to the skin, non-oily or greasy, and not have an objectionable texture or odor. Preferably, the formulation should have a desirable appearance, e.g., a homogeneous, clear solution. In addition, the formulation should be a true solution of tolnaftate, not a suspension. The solution should be stable at a wide range of temperatures to ensure that the tolnaftate does not precipitate from the solution after exposure to the extremes of temperature that the formulation may experience during shipping and storage.
Several commercially available antifungal formulations employ tolnaftate as the active ingredient, generally in an amount of 1% by weight. These formulations include powders, gels, creams, ointments, foams, aerosol powders and topical solutions. Examples of formulations of tolnaftate in solution form identified in the 1993 Physician's Desk Reference for Nonprescription Drugs include: Aftate.RTM. aerosol liquid, containing 36% alcohol (Schering-Plough HealthCare, Liberty Corner, New Jersey); Desenex.RTM. spray liquid, containing BHT, fragrance, isobutane, polyethylene glycol 400, SD alcohol 40-B (41% w/w) (Fisons Consumer Health, Rochester, N.Y.); Tinactin.RTM. 1% solution, containing BHT and PEG. This solution solidifies at low temperatures but liquifies readily on warming, according to the PDR (Schering-Plough HealthCare); and Ting.RTM. spray liquid, containing PHT, fragrance, isobutane (propellant), polyethylene glycol 400, SD alcohol 40-B (41% w/w) (Fisons Consumer Health).
Each of these products use high molecular weight PEG, which makes the product extremely oily and hinders skin penetration. In addition, the PEG takes a long time to dry on the skin surface. These products also include alcohol, which improves the drying and skin penetration properties, but does not overcome the disadvantages of the PEG.
Another commercial preparation is Proclearz (distributed by PPR Company, Brooklyn, N.Y. 11232). Proclearz is an antifungal liquid, particularly intended for topical treatment of fungal infections of the nail area. Proclearz includes 1% tolnaftate by weight in a solution containing acetone, water, tocophoryl acetate, propylene glycol and aloe vera gel. However, these solvents are inappropriate for extended use on skin as they may cause irritation and inflammation of the skin.